The invention relates to novel substituted 1,2-dialkyl-1-[1-[aryl(alkyl)oxyalkyl]piperidin-4-yl]-3-arylisothioureas, to their process of preparation and to their use as medicament.
A previous patent of the Applicant Company (WO-97/05134) claimed N-alkyl-N-[1-((xcfx89-aryloxyalkyl)piperidin-4-yl]-4H-3,1-benzothiazin-2-amine derivatives having therapeutic interest, particularly in the treatment of myocardial ischemia.
In order to bring about greater flexibility in the active molecule, capable of increasing its bioavailability and its solubility, the xe2x80x9copenxe2x80x9d compounds of the preceding series of benzothiazines were synthesized and allowed a novel class of compounds to be identified which is a subject-matter of the present invention: substituted 3-aryl-1-(piperidin-4-yl)-1-alkylisothioureas. Their pharmacological study has generally shown an activity greater than that of the cyclic series based on the in vitro test of contraction with veratrine of the rat isolated left atrium and in the ischemia test on the perfused isolated heart of the guinea pig.
The molecules of the present invention belong to the class of the N- and S-substituted 1-(1-aryl(alkyl)oxyalkylpiperidin-4-yl)-3-arylisothioureas of formula I: 
in which:
R1 and R2, which are identical or different, represent a saturated or unsaturated and branched or unbranched alkyl radical having from 1 to 7 carbon atoms,
R3 to R8, which are identical or different, represent:
a hydrogen,
a branched or unbranched alkyl having from 1 to 5 carbon atoms,
a branched or unbranched alkyloxy having from 1 to 5 carbon atoms,
a halo group,
a nitro group,
a hydroxyl group,
an acyl or acyloxy group having from 2 to 5 carbon atoms,
a dialkylamino group having from 1 to 5 carbon atoms,
a trifluoromethyl or trifluoromethoxyl group,
Z represents an oxygen or sulfur atom or a methylene,
m represents an integer varying from 0 to 4 inclusive,
n represents an integer between 2 and 7 inclusive.
The invention relates just as well, when they exist, to the pure R or S isomers or their mixtures.
The present invention includes the therapeutically acceptable inorganic or organic salts of the compounds of formula I and their possible hydrates.
The invention also relates to the process for the preparation of the claimed compounds and to their application as medicaments.
The molecules of the present invention possess noteworthy cytoprotective properties superior to those of the cyclic series of the family of the 4H-3,1-benzothiazin-2-amines and of the reference products, such as R56865.
The 1,2-dialkyl-1-[1-[aryl(alkyl)oxyalkyl]piperidin-4-yl]-3-arylisothioureas (I) are prepared in two stages from the N-alkyl-N-[1-(aryl)oxyalkyl-piperidin-4-yl]amines (II). The condensation of these amines (II) with an aryl isothiocyanate (III) according to the method of Kaye and Parris (J. Org. Chem., 1951, 16, 1859-1863) provides the corresponding thiourea (IV).
The S-alkylation of the latter is carried out by condensation of a haloalkane or of a dialkyl sulfate, either by adapting the method of Dupin S. and Pesson M. (Bull. Soc. Chim. Fr., 1963, 144-150) or by using calcium oxide to block the iodides formed by extrapolating the method of Honkenen. E. et al. (J. Med. Chem., 1983, 26, 1433-38), to give directly the compound I of the present invention (cf. Scheme 1). 
In the case where m=0 (Scheme 2), the intermediate amines (II) were prepared according to Ismaiel A. M. (J. Med. Chem., 1993, 36, 2519-2525) as described above in Patent WO 97/05134, using sodium triacetoxyborohydride as reducing agent in the final stage according to Abdel-Magid A. F. et al. (J. Org. Chem., 1996, 61, 3849-3862). 
If mxe2x89xa00, the etherification reaction (first stage, Scheme 2) can be carried out starting from the corresponding alcohol with 50% sodium hydroxide solution by PTC according to Burgstahler et al., J. Org. Chem., 1977, 42, 566-8.
The phenyl isothiocyanates which are not available commercially are prepared from the corresponding anilines by using thiocarbonyldiimidazole as described by Staab H. A. and Walther G. (Liebigs Ann. Chem., 1962, 567, 104-[lacuna]).